Crystalline forms of ozanimod and ozanimod hydrochloride, and processes for preparation thereof

ABSTRACT

The present disclosure is directed to novel crystalline forms of ozanimod and ozanimod hydrochloride, as well as preparation method thereof. Said crystalline forms of ozanimod and ozanimod hydrochloride can be used for treating autoimmune diseases, particularly used for preparing drugs for treating multiple sclerosis and ulcerative colitis. The crystalline forms of the present disclosure have one or more advantages in solubility, melting point, stability, dissolution, bioavailability and processability and provide new and better choices for the preparation of ozanimod drug product, and are very valuable for drug development.

TECHNICAL FIELD

The present disclosure relates to the field of pharmaceutical chemistry,particularly relates to crystalline forms of ozanimod and ozanimodhydrochloride, and processes for preparation thereof.

BACKGROUND

Ozanimod is a novel, oral, selective modulator ofsphingosine-1-phosphate 1 receptor (S1P1R) developed by Receptos for thetreatment of autoimmune diseases. ozanimod is in phase III trials in theUSA for the treatment of multiple sclerosis (MS) and ulcerative colitis(UC). Ozanimod has very excellent pharmacokinetics, pharmacodynamics andsafety data in clinical trials, which can perfectly meet thedifferentiated development strategy and is expected to be the bestsecond-generation SIP1R modulator drug. The chemical structure of thedrug is shown as formula (I).

A specific pharmaceutical activity is the basic prerequisite to befulfilled by a pharmaceutically active agent to be approved as amedicament on the market. However, there are a variety of additionalrequirements that a pharmaceutically active agent has to comply with.These requirements are based on various parameters which are connectedwith the nature of the active substance itself. Without beingrestricted, examples of these parameters are the chemical stability,solid-state stability and storage stability of the active substanceunder various environmental conditions, stability during production ofthe pharmaceutical composition and the stability of the active substancein the final drug products, etc.

The pharmaceutically active agent used for preparing the pharmaceuticalcompositions should be as pure as possible and its stability inlong-term storage must be guaranteed under various environmentalconditions. It is essential to prevent using pharmaceutical compositionswhich contain agent other than the actual active agent, for exampledecomposition products thereof. In such cases the content of activeagent in the drug might be less than that specified. In addition it isimportant that the pharmaceutically active agent should benon-hygroscopic, stable both to degradation and subsequent solid formchanges. If the pharmaceutically active agent is hygroscopic in thesense that it absorbs water (either slowly or over time), it is almostimpossible to reliably formulate the pharmaceutically active agent intoa drug as the amount of agent to be added to provide the same dosagewill vary greatly depending upon the degree of hydration. Furthermore,variations in hydration or solid form can lead to changes inphysicochemical properties, such as solubility or dissolution rate,which can in turn lead to inconsistent oral absorption of the patient.Preferably, therefore, a pharmaceutically active substance should beonly slightly hygroscopic.

Accordingly, chemical stability, solid-state stability, “shelf life” andmaterials handling properties (such as ease of solubilizing thecompound) of the pharmaceutically active substance are very importantfactors. In an ideal situation, the pharmaceutically active substanceand any compositions containing it should be capable of beingeffectively stored over appreciable periods of time, without exhibitinga significant change in the physicochemical properties of the activesubstance such as its activity, moisture content, solubility, solidform, etc. Further, the pharmaceutically active substance usually needsto be processed to achieve a particle size suitable for inhalation andany crystalline form must be stable during such processing so that theproperties of the final product are predictable and reliable. In short,in the production of commercially viable and pharmaceutically acceptablepharmaceutical compositions, it is desirable to provide thepharmaceutically active substance in a fully crystalline and stableform, wherever possible.

Different crystalline forms of the same solid chemical drug aresignificantly different in solubility and stability which can in turnaffect the absorption and bioavailability of the drug products.CN102762100A or US2011172202A1 disclosed the compound of formula (I),while there is no solid form or crystalline form of ozanimod disclosedin the prior art. The prior art has neither guidance nor inspiration forfinding the crystalline forms. Therefore, it is necessary to performcomprehensive polymorph screening of ozanimod to select a crystallineform which is the most suitable for drug development.

The inventors of the present disclosure have found several crystallineforms of ozanimod and a crystalline form of ozanimod hydrochloridethrough research process, which provides new choices for the preparationof ozanimod drug product.

SUMMARY

The present disclosure provides novel crystalline forms of ozanimod andozanimod hydrochloride, and processes for preparation and use thereof.

One objective of the present disclosure is to provide a crystalline formof ozanimod, designated as Form CS1.

The X-ray powder diffraction pattern of Form CS1 shows characteristicpeaks at 2 theta values of 12.1°±0.2°, 10.4°±0.2° and 4.2°±0.2° usingCuKα radiation.

Furthermore, the X-ray powder diffraction pattern of Form CS1 shows oneor two or three diffraction peaks at 2 theta values of 7.4°±0.2°,24.3°±0.2° and 17.7°±0.2°. Preferably, the X-ray powder diffractionpattern of Form CS1 shows three diffraction peaks at 2 theta values of7.4°±0.2°, 24.3°±0.2°, 17.7°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS1 shows oneor two or three characteristic peaks at 2 theta values of 12.8°±0.2°,21.5°±0.2° and 18.2°±0.2°. Preferably, the X-ray powder diffractionpattern of Form CS1 shows three diffraction peaks at 2 theta values of12.8°±0.2°, 21.5°±0.2° and 18.2°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS1 showscharacteristic peaks at 2 theta values of 4.2°±0.2°, 7.4°±0.2°,10.4°±0.2°, 12.1°±0.2°, 12.8°±0.2°, 17.7°±0.2°, 18.2°±0.2°, 21.5°±0.2°and 24.3°±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of FormCS1 is substantially as depicted in FIG. 1.

In a preferred embodiment, the differential scanning calorimetry (DSC)curve of Form CS1 shows the first endothermic peak when heated to around98° C. and the second endothermic peak when heated to around 134° C.,which is substantially as depicted in FIG. 2.

In a preferred embodiment, the thermal gravimetric analysis (TGA) curveof Form CS1 shows about 4.3% weight loss when heated to 150° C., whichis substantially as depicted in FIG. 3.

The present disclosure further provides the process for preparing FormCS1. The process comprises method 1) or method 2):

1) Suspending ozanimod hydrochloride into a solvent selected fromalcohols, ketones, esters and nitriles and the suspension becomes clearafter adding 1.0 to 1.5 (preferably 1.0) equivalent of sodium hydroxidesolution. Then, white solid precipitates from the solution afterstirring at room temperature for a period of time. Isolating the whitesolid by centrifugation, and then Form CS1 is obtained after drying theisolated solid. Said stirring time is at least 0.5 h, more preferably atleast 1 h, further more preferably 12 h; or

2) Suspending ozanimod in an alcohol, stirring, isolating and drying thesolid to obtain Form CS1 of ozanimod; wherein said stirring time is atleast 0.5 hour, more preferably at least 1 h, further more preferably 12h.

Furthermore, in method 1), said alcohol is methanol; said ketone isacetone; said ester is isopropyl acetate; said nitrile is acetonitrile.In method 2), said alcohol is methanol.

Another objective of the present disclosure is to provide a crystallineform of ozanimod, designated as Form CS2.

The X-ray powder diffraction pattern of Form CS2 shows characteristicpeaks at 2 theta values of 23.2°±0.2°, 18.5°±0.2° and 13.3°±0.2° usingCuKα radiation.

Furthermore, the X-ray powder diffraction pattern of Form CS2 shows oneor two or three diffraction peaks at 2 theta values of 15.9°±0.2°,30.0°±0.2° and 14.2°±0.2°. Preferably, the X-ray powder diffractionpattern of Form CS2 shows three diffraction peaks at 2 theta values of15.9°±0.2°, 30.0°±0.2° and 14.2°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS2 shows oneor two or three characteristic peaks at 2 theta values of 4.0°±0.2°,26.5°±0.2° and 17.7°±0.2°. Preferably, the X-ray powder diffractionpattern of Form CS2 shows three diffraction peaks at 2 theta values of4.0°±0.2°, 26.5°±0.2° and 17.7°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS2 showscharacteristic peaks at 2 theta values of 4.0°±0.2°, 13.3°±0.2°,14.2°±0.2°, 15.9°±0.2°, 17.7°±0.2°, 18.5°±0.2°, 23.2°±0.2°, 26.5°±0.2°and 30.0°±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of FormCS2 is substantially as depicted in FIG. 4.

In a preferred embodiment, the differential scanning calorimetry (DSC)curve of Form CS2 shows an endothermic peak when heated to around 134°C., which is substantially as depicted in FIG. 5.

In a preferred embodiment, the thermal gravimetric analysis (TGA) curveof Form CS2 shows about 1.1% weight loss when heated to 150° C., whichis substantially as depicted in FIG. 6.

The present disclosure further provides the process for preparing FormCS2. The process comprises method 1) or method 2):

1) The crystalline Form CS2 is prepared by heating Form CS1 to 100-130°C., or

2) Suspending ozanimod into a solvent selected from nitriles, ketones,esters, aromatic hydrocarbons, cyclic ethers and water, or a mixture ofsolvents selected from alcohols and water, ketones and water, amides andwater, and then stirring, isolating and drying the solid to obtain FormCS2 of ozanimod; said stirring time is at least 0.5 hour, morepreferably at least 1 h, further more preferably 12 h.

Furthermore, said heating temperature in method 1) is 110° C.

Furthermore, in method 2), said nitrile is acetonitrile; said ketone isacetone or methyl isobutyl ketone; said ester is ethyl acetate; saidaromatic hydrocarbons is toluene; said cyclic ether is2-methyltetrahydrofuran; said mixture of solvents is mixture of ethanoland water, acetone and water, or N, N-dimethylformamide and water.

Another objective of the present disclosure is to provide a crystallineform of ozanimod, designated as Form CS3.

The X-ray powder diffraction pattern of Form CS3 shows at least onecharacteristic peak at 2 theta values of 4.4°±0.2°, 5.7°±0.2°,7.8°±0.2°, 11.0°±0.2°, 13.0°±0.2°, 13.7°±0.2°, 17.0°±0.2°, 23.2°±0.2°,24.1°±0.2° and 26.0°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS3 showscharacteristic peaks at 2 theta values of 4.4°±0.2°, 13.0°±0.2°,26.0°±0.2° and 11.0°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS3 shows oneor two or three diffraction peaks at 2 theta values of 7.8°±0.2°,23.2°±0.2° and 17.0°±0.2°. Preferably, the X-ray powder diffractionpattern of Form CS3 shows three diffraction peaks at 2 theta values of7.8°±0.2°, 23.2°±0.2° and 17.0°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS3 shows oneor two characteristic peaks at 2 theta values of 13.7°±0.2° and24.1°±0.2°. Preferably, the X-ray powder diffraction pattern of Form CS3shows two diffraction peaks at 2 theta values of 13.7°±0.2° and24.1°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS3 shows oneor two characteristic peaks at 2 theta values of 5.7°±0.2° and24.1°±0.2°. Preferably, the X-ray powder diffraction pattern of Form CS3shows two diffraction peaks at 2 theta values of 5.7°±0.2° and24.1°±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of FormCS3 shows characteristic peaks at 2 theta values of 4.4°±0.2°,7.8°±0.2°, 11.0°±0.2°, 13.0°±0.2°, 13.7°±0.2°, 17.0°±0.2°, 23.2°±0.2°,24.1°±0.2° and 26.0°±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of FormCS3 is substantially as depicted in FIG. 7.

In a preferred embodiment, the differential scanning calorimetry (DSC)curve of Form CS3 shows the first endothermic peak when heated to around112° C., shows an exothermic peak when heated to around 121° C. andshows the second endothermic peak when heated to around 133° C. which issubstantially as depicted in FIG. 8.

In a preferred embodiment, the thermal gravimetric analysis (TGA) curveof Form CS3 shows about 3.1% weight loss when heated to 130° C., whichis substantially as depicted in FIG. 9.

In a preferred embodiment, the X-ray powder diffraction pattern of FormCS3 shows characteristic peaks at 2 theta values of 4.4°±0.2°,5.7°±0.2°, 7.8°±0.2°, 11.0°±0.2°, 13.0°±0.2°, 17.0°±0.2°, 23.2°±0.2°,24.1°±0.2° and 26.0°±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of FormCS3 is substantially as depicted in FIG. 53.

Another objective of the present disclosure is to provide the processfor preparing Form CS3 of ozanimod. The process comprises: addingozanimod into a solvent selected form alcohols, nitriles,dichloromethane, esters, sulfoxides or a mixture of glycol dimethylether and water, filtering, evaporating the filtrate and collecting thesolid to obtain Form CS3 of ozanimod.

Preferably, said alcohol is methanol; said nitrile is acetonitrile; saidester is isopropyl acetate; said sulfoxide is dimethyl sulfoxide.

Another objective of the invention is to provide a crystalline form ofozanimod, designated as Form CS5.

The X-ray powder diffraction pattern of Form CS5 shows characteristicpeaks at 2 theta values of 4.3°±0.2°, 6.8°±0.2° and 16.4°±0.2° usingCuKα radiation.

Furthermore, the X-ray powder diffraction pattern of Form CS5 shows oneor two or three diffraction peaks at 2 theta values of 21.6°±0.2°,8.5°±0.2° and 13.6°±0.2°. Preferably, the X-ray powder diffractionpattern of Form CS5 shows three diffraction peaks at 2 theta values of21.6°±0.2°, 8.5°±0.2° and 13.6°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS5 shows oneor two or three diffraction peaks at 2 theta values of 13.0°±0.2°,25.0°±0.2° and 26.0°±0.2°. Preferably, the X-ray powder diffractionpattern of Form CS5 shows three diffraction peaks at 2 theta values of13.0°±0.2°, 25.0°±0.2° and 26.0°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS5 showscharacteristic peaks at 2 theta values of 4.3°±0.2°, 6.8°±0.2°,8.5°±0.2°, 13.0°±0.2°, 13.6°±0.2°, 16.4°±0.2°, 21.6°±0.2°, 25.0°±0.2°and 26.0°±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of FormCS5 is substantially as depicted in FIG. 10.

In a preferred embodiment, the differential scanning calorimetry (DSC)curve of Form CS5 shows the first endothermic peak when heated to around65° C., shows an exothermic peak when heated to around 91° C. and showsthe second endothermic peak when heated to around 133° C. and which issubstantially as depicted in FIG. 11.

Another objective of the present disclosure is to provide the process ofpreparing Form CS5 of ozanimod. The process comprises adding the solidof ozanimod into cyclic ethers, filtering, evaporating the filtrate andcollecting the solid to obtain Form CS5 of ozanimod.

Furthermore, said cyclic ether is 2-methyltetrahydrofuran.

Another objective of the present disclosure is to provide a crystallineform of ozanimod, designated as Form CS6.

The X-ray powder diffraction pattern of Form CS6 shows characteristicpeaks at 2 theta values of 4.4°±0.2°, 24.5°±0.2°, 26.5°±0.2° and13.8°±0.2° using CuKα radiation.

Furthermore, the X-ray powder diffraction pattern of Form CS6 shows oneor two diffraction peaks at 2 theta values of 13.0°±0.2° and 25.4°±0.2°.Preferably, the X-ray powder diffraction pattern of Form CS6 shows twodiffraction peaks at 2 theta values of 13.0°±0.2° and 25.4°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS6 shows oneor two or three diffraction peaks at 2 theta values of 8.9°±0.2°,13.4°±0.2° and 11.0°±0.2°. Preferably, the X-ray powder diffractionpattern of Form CS6 shows three diffraction peaks at 2 theta values of8.9°±0.2°, 13.4°±0.2° and 11.0°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS6 showscharacteristic peaks at 2 theta values of 4.4°±0.2°, 8.9°±0.2°,11.0°±0.2°, 13.0°±0.2°, 13.4°±0.2°, 13.8°±0.2°, 24.5°±0.2°, 25.4°±0.2°and 26.5°±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of FormCS6 is substantially as depicted in FIG. 16.

In a preferred embodiment, the differential scanning calorimetry (DSC)curve of Form CS6 shows an exothermic peak when heated to around 110° C.and shows an endothermic peak when heated to around 135° C., which issubstantially as depicted in FIG. 13.

In a preferred embodiment, the thermal gravimetric analysis (TGA) curveof Form CS6 shows about 1.2% weight loss when heated to 120° C., whichis substantially as depicted in FIG. 14.

Another objective of the present disclosure is to provide the process ofpreparing Form CS6 of ozanimod. The process comprises adding the solidof ozanimod into a solvent selected from ketones, chloroform and thelike, filtering, evaporating the filtrate and collecting the solid toobtain Form CS6 of ozanimod.

Preferably, said ketone is acetone.

Another objective of the present disclosure is to provide apharmaceutical composition comprising a therapeutically amount ofozanimod Form CS1 or Form CS2 or a combination thereof andpharmaceutically acceptable carriers, diluents or excipients. Generally,mix or contact therapeutically a therapeutically amount of Form CS1 orForm CS2 or a combination thereof and one or more pharmaceuticallyacceptable excipients to make pharmaceutical composition or drugproducts, and the pharmaceutical composition or drug products areprepared by well-known method in the pharmaceutical field.

Ozanimod Form CS1 or Form CS2 or combinations thereof provided by thepresent disclosure can be used for preparing drugs for treatingautoimmune diseases, particularly used for preparing drug products fortreating multiple sclerosis and ulcerative colitis.

The present disclosure also provides a pharmaceutical compositioncomprising a therapeutically amount of ozanimod Form CS3, Form CS5, FormCS6 or combinations thereof and pharmaceutically acceptable carriers,diluents or excipients. Generally, mix or contact therapeutically aneffective amount of Form CS3, Form CS5, Form CS6 or a combinationthereof and one or more pharmaceutically acceptable excipients to makepharmaceutical composition or drug products, and the pharmaceuticalcomposition or drug products are prepared by well-known method in thepharmaceutical field.

Ozanimod Form CS3, Form CS5 or Form CS6 or combinations thereof providedby present disclosure can be used for preparing drugs of selectivemodulator of sphingosine-1-phosphate 1 receptor.

Ozanimod Form CS3, Form CS5 or Form CS6 or combinations thereof providedby present disclosure can be used for preparing drugs for treatingautoimmune diseases, particularly used for preparing drug products fortreating multiple sclerosis and ulcerative colitis.

The present disclosure further provides a pharmaceutical compositioncomprising a therapeutically amount of ozanimod Form CS1, Form CS2, FormCS3, Form CS5, Form CS6 or combinations thereof and pharmaceuticallyacceptable carriers, diluents or excipients.

Furthermore, ozanimod Form CS1, Form CS2, Form CS3, Form CS5, Form CS6or combinations thereof can be used for preparing drugs of selectivemodulator of sphingosine-1-phosphate 1 receptor.

Ozanimod Form CS1, Form CS2, Form CS3, Form CS5, Form CS6 orcombinations thereof can be used for preparing drugs for treatingulcerative colitis.

Ozanimod Form CS1, Form CS2, Form CS3, Form CS5, Form CS6 orcombinations thereof can be used for preparing drugs for treatingmultiple sclerosis.

Another objective of the present disclosure is to provide a crystallineform of ozanimod hydrochloride, designated as Form CS1 of ozanimodhydrochloride.

The X-ray powder diffraction pattern of Form CS1 of ozanimodhydrochloride shows characteristic peaks at 2 theta values of26.1°±0.2°, 24.4°±0.2° and 20.1°±0.2° using CuKα radiation.

Furthermore, the X-ray powder diffraction pattern of Form CS1 ofozanimod hydrochloride shows one or two or three diffraction peaks at 2theta values of 3.9°±0.2°, 21.1°±0.2° and 7.9°±0.2°. Preferably, theX-ray powder diffraction pattern of Form CS1 of ozanimod hydrochlorideshows three diffraction peaks at 2 theta values of 3.9°±0.2°, 21.1°±0.2°and 7.9°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS1 ofozanimod hydrochloride shows one or two or three diffraction peaks at 2theta values of 11.9°±0.2°, 19.6°±0.2° and 13.8°±0.2°. Preferably, theX-ray powder diffraction pattern of Form CS1 of ozanimod hydrochlorideshows diffraction peaks at 2 theta values of 11.9°±0.2°, 19.6°±0.2° and13.8°±0.2°.

Furthermore, the X-ray powder diffraction pattern of Form CS1 ofozanimod hydrochloride shows characteristic peaks at 2 theta values of3.9°±0.2°, 7.9°±0.2°, 11.9°±0.2°, 13.8°±0.2°, 19.6°±0.2°, 20.1°±0.2°,21.1°±0.2°, 24.4°±0.2° and 26.1°±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of FormCS1 of hydrochloride is substantially as depicted in FIG. 17.

In a preferred embodiment, the X-ray powder diffraction pattern of FormCS1 of hydrochloride is substantially as depicted in FIG. 20.

In a preferred embodiment, the differential scanning calorimetry (DSC)curve of Form CS1 of hydrochloride shows an endothermic peak when heatedto around 238° C., which is substantially as depicted in FIG. 18.

In a preferred embodiment, the thermal gravimetric analysis (TGA) curveof Form CS1 of hydrochloride shows about 1.1% weight loss when heated to150° C., which is substantially as depicted in FIG. 19.

Another objective of the present disclosure is to provide the process ofpreparing Form CS1 of ozanimod hydrochloride. The process comprisesmethod 1) or method 2) or method 3) or method 4),

1) Adding ozanimod hydrochloride into ethers and stirring for a periodof time at a certain temperature (4-50° C., preferably 25° C.),filtering and drying to obtain white solid; said stirring time is atleast 1 hour, preferably at least 24 hours, more preferably seven days;or

2) Dissolving ozanimod hydrochloride into a solvent selected fromalcohols and esters or a mixture of solvents thereof, evaporating atroom temperature to obtain white solid; said “evaporation time” usuallymeans the time or longer than the time for solid precipitation. Theevaporation time is preferably 0.5 day to 14 days, more preferably 7days; or

3) Dissolving ozanimod hydrochloride into a solvent selected from amidesor a mixture of solvents thereof, then placing the solution in a systemcontaining anti-solvent of ozanimod hydrochloride for liquid vapordiffusion at room temperature, filtering and drying to obtain whitesolid; said “diffusion time” usually means the time or longer than thetime for solid precipitation. The diffusion time is preferably 1 day to14 days, more preferably 7 days; or

4) Dissolving ozanimod hydrochloride into a mixture of alcohols andwater to form a supersaturated solution, ozanimod hydrochloride is fullydissolved at 25-80° C. (preferably 50° C.), and then filtering, coolingthe filtrate for precipitation, filtering and drying to obtain whitesolid of Form CS1 of ozanimod hydrochloride.

Another objective of the present disclosure is to provide apharmaceutical composition comprising a therapeutically amount of FormCS1 of ozanimod hydrochloride and pharmaceutically acceptable carriers,diluents or excipients. Generally, mix or contact therapeutically aneffective amount of Form CS1 of ozanimod hydrochloride and one or morepharmaceutically acceptable excipients to make pharmaceuticalcomposition or drug products, and the pharmaceutical composition or drugproducts are prepared by well-known method in the pharmaceutical field.

Furthermore, Form CS1 of ozanimod hydrochloride provided by presentdisclosure can be used for preparing drugs for treating autoimmunediseases, particularly used for preparing drug products for treatingmultiple sclerosis and ulcerative colitis.

Said “room temperature” in the present disclosure is not an exacttemperature value and refers to 10-30° C.

The reaction time of “evaporating” and “diffusion” in the presentdisclosure refers to the time before solid precipitation or longer.

Said “stirring” is accomplished by using a conventional method in thefield such as a magnetic stirring or a mechanical stirring and thestirring speed is 50 to 1800 r/min, preferably is 300 to 900 r/min.

Said “separation” is accomplished by using a conventional method in thefield such as centrifugation or filtration. The operation of“centrifugation” is as follows: the sample to be separated is placedinto the centrifuge tube, and then centrifuged at a rate of 10000 r/minuntil the solid all sink to the bottom of the tube.

Said “drying” is accomplished at room temperature or a highertemperature. The drying temperature is from room temperature to about60° C., or to 40° C., or to 50° C. The drying time can be 2 to 48 hours,or overnight. Drying is accomplished in a fume hood, oven or vacuumoven.

Said “evaporating” is accomplished by using a conventional method in thefield. For example, slow evaporation is to seal the container with asealing film and puncture holes for evaporation. Rapid evaporation is toplace the container open for evaporation.

Said “polymer” is a mixture of equal masses of polycaprolactone,polyoxyethylene, polymethyl methacrylate, sodium alginate, andhydroxyethyl cellulose.

The beneficial effects of the present disclosure are as follows:

At present, no patent or literature has disclosed the crystalline formof ozanimod and inventors of the present disclosure broke through thisdifficult problem and several novel crystalline forms of ozanimodsuitable for the drug development are found.

The crystalline forms and crystalline form of hydrochloride provided bythe present disclosure have advantages in solubility, melting point,stability, dissolution, bioavailability and processability. As for thecrystalline Form CS1, Form CS2, Form CS3, Form CS5, Form CS6 and FormCS1 of the hydrochloride, the hygroscopicity is low, stability is good,solubility meets the medicinal requirements, particle size distributionis uniform and the dispersion is good. These advantages help to simplifythe post-treatment process of preparing drugs and provide new and betterchoices for the preparation of ozanimod drug products, which are veryimportant for drug development.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an XRPD pattern of Form CS1 obtained in Example 1.

FIG. 2 shows a DSC curve of Form CS1 obtained in Example 1.

FIG. 3 shows a TGA curve of Form CS1 obtained in Example 1.

FIG. 4 shows an XRPD pattern of Form CS2 obtained in Example 3.

FIG. 5 shows a DSC curve of Form CS2 obtained in Example 3.

FIG. 6 shows a TGA curve of Form CS2 obtained in Example 3.

FIG. 7 shows an XRPD pattern of Form CS3 obtained in Example 5.

FIG. 8 shows a DSC curve of Form CS3 obtained in Example 5.

FIG. 9 shows a TGA curve of Form CS3 obtained in Example 5.

FIG. 10 shows an XRPD pattern of Form CS5 obtained in Example 8.

FIG. 11 shows a DSC curve of Form CS5 obtained in Example 8.

FIG. 12 shows an XRPD pattern of Form CS6 obtained in Example 9.

FIG. 13 shows a DSC curve of Form CS6 obtained in Example 10.

FIG. 14 shows a TGA curve of Form CS6 obtained in Example 10.

FIG. 15 shows an XRPD pattern of Form CS3 obtained in Example 6.

FIG. 16 shows an XRPD pattern of Form CS6 obtained in Example 10.

FIG. 17 shows an XRPD pattern of Form CS1 of hydrochloride.

FIG. 18 shows a DSC curve of Form CS1 of hydrochloride obtained inExample 11.

FIG. 19 shows a TGA curve of Form CS1 of hydrochloride obtained inExample 11.

FIG. 20 shows an XRPD pattern of Form CS1 of hydrochloride obtained inExample 11.

FIG. 21 shows an XRPD pattern of Form CS1 of hydrochloride obtained inExample 12.

FIG. 22 shows an XRPD pattern of Form CS1 of hydrochloride obtained inExample 13.

FIG. 23 shows an XRPD pattern of Form CS1 of hydrochloride obtained inExample 14.

FIG. 24 shows an XRPD pattern of Form CS1 of hydrochloride obtained inExample 15.

FIG. 25 shows a DVS plot of Form CS1 in Example 16.

FIG. 26 shows a DVS plot of Form CS2 in Example 17.

FIG. 27 shows a DVS plot of Form CS3 in Example 18.

FIG. 28 shows a DVS plot of Form CS5 in Example 19.

FIG. 29 shows a DVS plot of Form CS6 in Example 20.

FIG. 30 shows a DVS plot of Form CS1 of hydrochloride in Example 21.

FIG. 31 shows an XRPD comparison pattern of Form CS1 before and afterstability test in Example 22.

FIG. 32 shows an XRPD comparison pattern of Form CS2 before and afterstability test in Example 23.

FIG. 33 shows an XRPD comparison pattern of Form CS3 before and afterstability test in Example 24.

FIG. 34 shows an XRPD comparison pattern of Form CS5 before and afterstability test in Example 25.

FIG. 35 shows an XRPD comparison pattern of Form CS6 before and afterstability test in Example 26.

FIG. 36 shows an XRPD comparison pattern of Form CS1 of hydrochloridebefore and after stability test in Example 27.

FIG. 37 shows a PSD diagram of Form CS1 in Example 28.

FIG. 38 shows a PSD diagram of Form CS2 in Example 28.

FIG. 39 shows a PSD diagram of Form CS3 in Example 28.

FIG. 40 shows a PSD diagram of Form CS5 in Example 28.

FIG. 41 shows a PSD diagram of Form CS6 in Example 28.

FIG. 42 shows a PSD diagram of Form CS1 of hydrochloride in Example 28.

FIG. 43 shows a PLM image of Form CS1 in Example 28.

FIG. 44 shows a PLM image of Form CS2 in Example 28.

FIG. 45 shows a PLM image of Form CS3 in Example 28.

FIG. 46 shows a PLM image of Form CS5 in Example 28.

FIG. 47 shows a PLM image of Form CS6 in Example 28.

FIG. 48 shows a PLM image of Form CS1 of hydrochloride in Example 28.

FIG. 49 shows an XRPD comparison pattern of Form CS3 before and aftergrinding test in Example 31.

FIG. 50 shows an XRPD comparison pattern of Form CS5 before and aftergrinding test in Example 31.

FIG. 51 shows an XRPD comparison pattern of Form CS6 before and aftergrinding test in Example 31.

FIG. 52 shows an XRPD comparison pattern of Form CS1 of hydrochloridebefore and after grinding test in Example 31.

FIG. 53 shows an XRPD pattern of Form CS3 in Example 7.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure is further illustrated by the following examplesin detail, but is not intended to limit the scope of the presentdisclosure. The skilled in the art can make improvements to the processof preparation and the instruments used within the scope of the claims,and those improvements should be considered as falling into the scope ofthe present disclosure. Therefore, the protective scope of the presentdisclosure patent should be defined by the claims.

In the following examples, the test method is generally implementedaccording to a conventional condition or a condition recommended bymanufacturer.

The abbreviations used in the disclosure are explained as follows:

XRPD: X-ray Powder Diffraction

DSC: Differential Scanning calorimetry

TGA: Thermal Gravimetric Analysis

DVS: Dynamic Vapor Sorption

PSD: Particle Size Distribution

PLM: Polarized Light microscopy

X-ray powder diffraction pattern in the present disclosure was acquiredby a Panalytical Empyrean X-ray powder diffractometer. The parameters ofthe X-ray powder diffraction method of the present disclosure were asfollows:

X-ray Reflection: Cu, Kα

Kα1 (Å): 1.540598; Kα2 (Å): 1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 (kV)

Current: 40 (mA)

Scan range: from 3.0 degree to 40.0 degree

Differential scanning calorimetry (DSC) data in the present disclosurewere acquired by a TA Q2000. The parameters of the differential scanningcalorimetry (DSC) method of the present disclosure were as follow:

Heating rate: 10° C./min

Purge gas: nitrogen

Thermal gravimetric analysis (TGA) data in the present disclosure wereacquired by a TA Q5000. The parameters of the thermal gravimetricanalysis (TGA) method of the present disclosure were as follow:

Heating rate: 10° C./min

Purge gas: nitrogen

Dynamic Vapor Sorption (DVS) is measured via an SMS (Surface MeasurementSystems Ltd.) intrinsic DVS. Typical Parameters for DVS test are asfollows:

Temperature: 25° C.

Gas and flow rate: N₂, 200 mL/min

dm/dt: 0.002%/min

RH range: 0% RH to 95% RH

The particle size distribution test in the present disclosure isacquired by the S3500 laser particle size analyzer of Microtrac.Microtrac S3500 is equipped with the SDC (Sample Delivery Controller).The test is carried out by wet process, and the dispersion medium isIsopar G The parameters are as follow:

Size distribution: Volume Run Time: 10 s Dispersion medium: Isopar GParticle coordinates: Standard Run Number: Average of 3 runs Fluidrefractive index: 1.42 Particle Transparency: Trans Residuals: EnabledParticle refractive index: 1.5 Flow rate: 60%* Particle shape: IrregularFiltration: Enabled Ultrasonication power: 30 W Ultrasonication time: 30s *: Flow rate 60% is 60% of 65 mL/s.

Raw materials of ozanimod and/or a hydrochloride thereof used in thefollowing examples are prepared by methods disclosed in CN102762100A.

Example 1

Preparation of Form CS1 of Ozanimod:

About 2.0 g of ozanimod hydrochloride was added into a 150-mL glass vialfollowed by adding 100 mL of methanol to form a suspension at roomtemperature. The suspension became clear after 7.0 mL of sodiumhydroxide solution (32 mg/mL) was added dropwise. And then, white solidprecipitated out after stirring at room temperature for 12 hours. Thesuspension was centrifuged and dried to isolate solid.

The obtained solid was identified as Form CS1. The XRPD data of thesolid prepared in this example are listed in Table 1. The XRPD patternis displayed in FIG. 1. The DSC curve is displayed in FIG. 2. The TGAcurve is displayed in FIG. 3.

TABLE 1 Relative 2theta d spacing intensity % 4.24 20.83 53.60 7.3712.00 20.87 8.78 10.07 3.91 10.45 8.46 60.36 12.07 7.33 100.00 12.826.90 9.66 14.19 6.24 6.17 16.17 5.48 1.63 17.19 5.16 4.96 17.65 5.029.86 18.22 4.87 7.35 18.69 4.75 1.61 20.18 4.40 2.40 21.51 4.13 9.6421.95 4.05 2.44 22.35 3.98 5.65 22.82 3.90 3.25 23.51 3.78 2.32 24.353.66 19.15 24.74 3.60 3.72 25.69 3.47 0.86 26.63 3.35 0.75 27.30 3.271.49 28.60 3.12 1.52 30.90 2.89 2.80 31.26 2.86 1.01 32.44 2.76 0.5733.63 2.67 1.87 34.77 2.58 0.91 36.41 2.47 1.13 39.25 2.30 1.49

Use the preparation method of example 1, about 10 mg of ozanimodhydrochloride was suspended in methanol, acetone, isopropyl acetate oracetonitrile. The suspension became clear after 1.0-1.5 equivalent ofsodium hydroxide solution was added. Then white solid precipitated outafter stirring the solution at room temperature for 12 hours. Thesuspension was centrifuged to obtain solid. The solid was dried undervacuum. The obtained solid was identified as Form CS1 and its XRPDpattern was same as FIG. 1.

Example 2

Preparation of Form CS1 of Ozanimod:

About 10 mg of ozanimod and 0.5 mL of methanol was added into a 1.5-mLglass vial. The suspension was stirred at room temperature for 24 hours.The obtained white solid was identified as Form CS1 and its XRPD patternwas substantially the same as FIG. 1.

Example 3

Preparation of Form CS2 of Ozanimod:

About 20 mg of Form CS1 of ozanimod was added into a 3-mL glass vial.And then, the solid was dried under vacuum at 110° C. for 1 hour. Theobtained white solid was identified as Form CS2.

The XRPD data of the solid prepared in this example are listed in Table2. The XRPD pattern is displayed in FIG. 4. The DSC curve is displayedin FIG. 5. The TGA curve is displayed in FIG. 6.

TABLE 2 Relative 2theta d spacing intensity % 3.96 22.33 20.48 7.9511.12 11.39 12.02 7.36 4.10 13.33 6.64 35.96 14.16 6.25 21.29 15.89 5.5819.75 17.72 5.00 12.52 18.49 4.80 36.64 20.08 4.42 11.25 20.77 4.28 4.5921.36 4.16 7.46 21.53 4.13 8.77 22.56 3.94 8.50 23.19 3.84 100.00 24.223.67 4.08 24.97 3.57 3.68 26.47 3.37 17.30 27.46 3.25 3.66 28.40 3.141.16 29.98 2.98 28.43 31.45 2.84 1.01 32.19 2.78 2.21 34.53 2.60 0.6937.45 2.40 0.61 38.43 2.34 0.73 39.50 2.28 1.41

Example 4a-4j

Preparation of Form CS2 of Ozanimod:

As shown in Table 3, about 10 mg of ozanimod was added into 1.5-mL galssvials followed by adding a certain volume of solvents to formsuspensions. These suspensions were stirred at room temperature for 24hours. The obtained solids were collected and labeled as samples 1-10.Samples 1-10 were identified as Form CS2. The X-ray powder diffractionpatterns of these samples are same as FIG. 4, which shows characteristicpeaks at 2 theta values of 4.0°±0.2°, 13.3°±0.2°, 14.2°±0.2°,15.9°±0.2°, 17.7°±0.2°, 18.5°±0.2°, 23.2°±0.2°, 26.5°±0.2° and30.0°±0.2°.

TABLE 3 Mass Volume Solid Example (mg) Solvent (mL) Form Label 4a 10.2Acetonitrile 0.5 CS2 Sample 1 4b 10.3 Acetone 0.5 CS2 Sample 2 4c 10.3Methyl isobutyl ketone 0.5 CS2 Sample 3 4d 10.8 Ethyl acetate 0.5 CS2Sample 4 4e 9.8 Toluene 0.5 CS2 Sample 5 4f 9.7 2-Methyltetrahydrofuran0.5 CS2 Sample 6 4g 10.0 Water 0.5 CS2 Sample 7 4h 10.4 Ethanol/water(19:1, v/v) 0.5 CS2 Sample 8 4i 9.4 Dimethylformamide/water 0.5 CS2Sample 9 (3:2,v/v) 4j 9.7 Acetone/water (9:1,v/v) 0.5 CS2 Sample10

Example 5

Preparation of Form CS3 of Ozanimod:

About 5.0 mg of ozanimod was added into a 3-mL galss vial followed byadding 0.4 mL of dichloromethane. The mixture was filtered and about 0.2mg of polymer was added into the clear solution. And then the solutionwas slowly evaporated at room temperature until white solid wasobtained. The obtained white solid was identified as Form CS3.

The XRPD data of the solid prepared in this example are listed in Table4. The XRPD pattern is displayed in FIG. 7. The DSC curve is displayedin FIG. 8. The TGA curve is displayed in FIG. 9.

TABLE 4 Relatively 2theta d spacing intensity % 3.04 29.02 12.88 4.4319.93 100.00 7.84 11.28 16.58 8.92 9.92 10.16 11.03 8.02 15.96 12.966.83 83.06 13.43 6.59 11.89 13.72 6.46 33.05 15.80 5.61 3.44 16.57 5.355.55 17.00 5.21 19.94 17.98 4.93 4.44 18.38 4.83 4.34 19.83 4.48 6.9320.06 4.43 8.40 20.57 4.32 5.85 21.53 4.13 7.15 21.98 4.04 6.11 22.563.94 8.12 23.17 3.84 23.33 24.09 3.69 14.77 25.14 3.54 12.77 26.00 3.4341.57 26.68 3.34 9.46 28.42 3.14 6.82 30.67 2.91 1.27 33.98 2.64 0.5335.51 2.53 0.79

Example 6

Preparation of Form CS3 of Ozanimod:

About 5 mg of ozanimod solid was added into a 3-mL galss vial followedby adding 1.0 mL of acetonitrile. The mixture was filtered and fastevaporated at room temperature until white solid was obtained.

The obtained white solid was identified as Form CS3. The XRPD data ofthe solid prepared in this example are listed in Table 5. The XRPDpattern is displayed in FIG. 15.

TABLE 5 Relatively 2theta d spacing intensity % 4.44 19.89 94.06 5.2016.98 3.53 7.86 11.25 22.55 8.93 9.90 15.72 9.38 9.433 4.17 11.05 8.0018.33 12.97 6.83 100.00 13.73 6.45 41.96 14.44 6.13 7.95 15.78 5.62 8.1016.14 5.49 4.53 17.01 5.21 19.74 18.22 4.87 2.42 20.07 4.42 8.54 20.264.39 3.28 20.50 4.34 6.66 21.53 4.13 7.83 21.99 4.04 4.91 22.60 3.9311.03 23.18 3.84 24.17 24.08 3.70 14.26 25.15 3.54 11.64 26.03 3.4239.79 26.63 3.35 5.94 28.42 3.14 12.28 30.39 2.94 4.29 37.15 2.42 5.9237.37 2.41 4.67

Use the preparation method of example 6, Form CS3 can be prepared byevaporation in methanol, isopropyl acetate and dimethyl sulfoxide.

Example 7

Preparation of Form CS3 of Ozanimod:

About 15 mg of ozanimod solid was added into a 3-mL galss vial followedby adding 1.0 mL of solvent mixture of glycol dimethyl ether and water(1:1, v/v). The mixture was filtered and slowly evaporated at roomtemperature until white solid was obtained.

The obtained white solid was identified as Form CS3, which showscharacteristic peaks at 2 theta values of 4.42°, 5.70°, 7.85°, 11.06°,12.99°, 17.04°, 23.21°, 24.11° and 26.04°. The XRPD pattern is displayedin FIG. 53.

Example 8

Preparation of Form CS5 of Ozanimod:

About 10 mg of ozanimod solid was added into a 3-mL galss vial followedby adding 2.4 mL of 2-methyltetrahydrofuran. The mixture was filteredand fast evaporated at room temperature to obtain white solid.

The obtained white solid was identified as Form CS5. The XRPD data ofthe solid prepared in this example are listed in Table 6. The XRPDpattern is displayed in FIG. 10. The DSC curve is displayed in FIG. 11.

TABLE 6 Relatively 2theta d spacing intensity % 4.25 20.80 100.00 6.7613.08 3.43 7.71 11.47 1.36 8.55 10.34 13.99 10.79 8.20 1.07 12.96 6.8334.38 13.61 6.51 9.98 14.42 6.14 1.40 15.13 5.85 1.00 16.39 5.41 3.8416.86 5.26 4.05 17.29 5.13 2.70 18.37 4.83 0.78 19.57 4.54 2.18 20.484.34 5.14 21.60 4.12 8.34 22.52 3.95 1.56 23.20 3.83 1.88 24.04 3.704.04 24.98 3.56 4.18 26.03 3.42 5.50 27.06 3.30 3.14 28.35 3.15 0.6429.00 3.08 0.35 30.27 2.95 0.47 31.14 2.87 0.58 32.77 2.73 0.49 35.242.55 0.49 37.31 2.41 0.16

Example 9

Preparation of Form CS6 of Ozanimod:

About 15 mg of ozanimod was weighed into a 3-mL galss vial followed byadding about 0.2 mL of chloroform. The mixture was filtered and fastevaporated at room temperature to obtain white solid.

The obtained white solid was identified as Form CS6. The XRPD data ofthe solid prepared in this example are listed in Table 7. The XRPDpattern is displayed in FIG. 12.

TABLE 7 Relatively 2theta d spacing intensity % 4.45 19.88 100.00 7.8611.24 6.23 8.89 9.95 10.03 11.03 8.02 7.43 13.01 6.81 26.15 13.37 6.628.34 13.75 6.44 11.19 14.89 5.95 0.81 15.49 5.72 1.94 15.79 5.61 1.5216.94 5.23 3.00 17.12 5.18 4.44 17.87 4.96 2.72 19.06 4.66 1.52 19.224.62 1.51 20.13 4.41 3.22 21.55 4.12 2.16 22.40 3.97 3.75 22.82 3.902.11 23.58 3.77 2.04 24.51 3.63 5.93 25.42 3.50 4.55 26.22 3.40 2.1926.52 3.36 5.03 27.06 3.30 0.91 27.86 3.20 1.37 28.32 3.15 0.61 28.863.09 0.51 30.04 2.97 0.34 32.15 2.78 0.22 33.55 2.67 0.33 37.44 2.400.25

Using the preparation method of example 9, Form CS6 can be prepared byevaporating in acetone.

Example 10

Preparation of Form CS6 of Ozanimod:

About 5 mg of ozanimod solid was added into a 3-mL galss vial followedby adding 0.4 mL of chloroform. The mixture was filtered and fastevaporated at room temperature to obtain white solid.

The obtained white solid was identified as Form CS6. The XRPD data ofthe solid prepared in this example are listed in Table 8. The XRPDpattern is displayed in FIG. 16.

10 mg of CS6 was re-prepared using the method of example 10, which wasused for DSC and TGA characterization. The DSC curve is displayed inFIG. 13. The TGA curve is displayed in FIG. 14.

TABLE 8 Relatively 2theta d spacing intensity % 4.44 19.88 100.00 7.8611.25 11.49 8.89 9.94 19.71 11.03 8.02 12.60 13.00 6.81 53.68 13.37 6.6215.73 13.75 6.44 21.24 14.95 5.93 2.05 15.44 5.74 2.80 15.78 5.62 1.8417.08 5.19 4.53 17.87 4.96 5.38 19.11 4.64 2.07 20.06 4.43 4.31 21.554.12 4.26 22.43 3.96 6.47 23.44 3.80 1.73 24.51 3.63 3.95 25.34 3.513.19 26.18 3.40 3.93 26.61 3.35 4.89 27.75 3.22 1.62 28.94 3.09 1.0130.18 2.96 0.66 32.42 2.76 0.81 36.51 2.46 0.47 37.42 2.40 0.33 38.942.31 0.76 39.35 2.29 0.61

Example 11

Preparation of Form CS1 of Ozanimod Hydrochloride:

10.1 mg of ozanimod hydrochloride was added into a 1.5-mL galss vialfollowed by adding 0.5 mL of 2-methyltetrahydrofuran to form asuspension. The suspension was stirred at room temperature for 1 week,then white solid was obtained after centrifugation and drying.

The obtained white solid was identified as Form CS1 of ozanimodhydrochloride. The XRPD data of the solid prepared in this example arelisted in Table 9. The XRPD pattern is displayed in FIG. 20. The DSCcurve is displayed in FIG. 18. The TGA curve is displayed in FIG. 19.

TABLE 9 Relatively 2theta d spacing intensity % 3.93 22.51 58.37 7.9311.14 23.15 11.95 7.41 21.69 12.56 7.05 70.18 13.02 6.80 82.51 13.776.43 85.16 14.86 5.96 6.06 15.97 5.55 21.05 16.91 5.24 30.15 18.19 4.8820.42 18.54 4.79 4.12 18.79 4.72 33.76 19.59 4.53 38.99 20.07 4.42 46.2721.11 4.21 64.20 22.75 3.91 26.66 23.22 3.83 10.34 24.41 3.65 100.0026.10 3.41 93.31 27.11 3.29 9.18 27.90 3.20 20.23 28.31 3.15 6.44 28.993.08 8.18 29.85 2.99 7.60 31.11 2.88 5.90 31.55 2.84 11.45 33.37 2.693.80 35.35 2.54 5.57 36.66 2.45 6.89

Example 12

Preparation of Form CS1 of Ozanimod Hydrochloride:

6.0 mg of ozanimod hydrochloride was added into a 1.5-mL galss vialfollowed by adding 0.5 mL of methanol. The solution was filtered andevaporated quickly at room temperature for 1 week to obtain solid.

The obtained solid was identified as Form CS1 of ozanimod hydrochloride.The XRPD data of the solid prepared in this example are listed in Table10. The XRPD pattern is displayed in FIG. 21.

TABLE 10 Relatively 2theta d spacing intensity % 3.95 22.37 65.70 7.9411.13 39.57 8.57 10.32 2.24 11.97 7.39 42.06 12.55 7.05 9.32 13.02 6.8010.98 13.78 6.438 12.03 15.33 5.78 1.81 15.99 5.54 3.50 18.78 4.73 7.4719.61 4.53 3.45 20.10 4.42 100.00 21.12 4.21 13.94 22.73 3.91 2.92 24.423.65 17.01 25.02 3.56 12.72 26.14 3.41 19.94 27.30 3.27 2.47 27.94 3.193.98 28.34 3.15 2.68 29.03 3.08 2.70 29.82 3.00 1.74 31.03 2.88 2.5331.63 2.83 5.10 32.52 2.75 2.27 33.49 2.68 1.55 35.28 2.54 1.87 36.692.45 18.83 37.44 2.40 0.94 38.94 2.31 1.26 39.35 2.29 1.87

Example 13

Preparation of Form CS1 of Ozanimod Hydrochloride:

5.5 mg of ozanimod hydrochloride was added into a 1.5-mL galss vialfollowed by adding 0.8 mL of solvent mixture of methanol and ethylacetate (3:1, v/v) and 0.2 mg of polymer. The mixture was fastevaporated at room temperature for 1 week to obtain a solid.

The obtained solid was identified as ozanimod hydrochloride Form CS1.The XRPD data of the solid prepared in this example are listed in Table11. The XRPD pattern is displayed in FIG. 22.

TABLE 11 Relatively 2theta d spacing intensity % 3.90 22.64 100.00 7.9211.16 29.74 10.98 8.06 3.07 11.94 7.41 33.69 12.56 7.05 73.32 13.05 6.7878.29 13.78 6.43 78.88 14.94 5.93 6.31 16.04 5.52 17.30 16.96 5.23 14.4718.21 4.87 11.10 18.76 4.73 29.38 19.63 4.53 30.08 20.09 4.42 62.8321.13 4.20 51.45 22.74 3.91 20.95 24.42 3.65 70.20 24.99 3.56 20.3226.12 3.41 67.91 27.99 3.19 13.24 29.06 3.07 8.71 29.82 3.00 10.52 31.672.83 11.02 35.31 2.54 3.40 36.72 2.45 9.56 39.04 2.31 1.86

Example 14

Preparation of Form CS1 of Ozanimod Hydrochloride:

5.9 mg of ozanimod hydrochloride solid was added into a 1.5-mL galssvial followed by adding 0.3 mL of dimethylacetamide. The clear solutionwas placed into a 20-mL glass vial containing 5 mL of tetrahydrofuranfor liquid vapor diffusion for 1 week. Then the obtained suspension wasfiltered and dryed to obtain white solid.

The obtained white solid was identified as ozanimod hydrochloride FormCS1. The XRPD data of the solid prepared in this example are listed inTable 12. The XRPD pattern is displayed in FIG. 23.

TABLE 12 Relatively 2theta d spacing intensity % 3.94 22.42 29.02 7.9411.13 40.24 8.59 10.30 6.70 10.08 8.78 3.14 11.98 7.39 43.32 12.56 7.0530.75 13.03 6.79 34.04 13.78 6.42 38.84 15.31 5.79 2.91 15.96 5.55 12.4616.95 5.23 4.31 17.31 5.12 2.90 18.22 4.87 2.15 18.79 4.72 20.42 19.624.52 8.57 20.10 4.42 100.00 21.08 4.22 21.17 22.03 4.04 4.56 22.73 3.915.82 24.40 3.65 30.21 25.01 3.56 16.38 25.47 3.50 3.80 26.13 3.41 34.9426.77 3.33 4.27 27.02 3.30 3.66 27.30 3.27 5.18 27.90 3.20 6.81 29.013.08 2.92 29.98 2.98 3.94 31.07 2.88 2.48 31.57 2.83 6.30 32.48 2.762.04 32.96 2.72 2.06 34.21 2.62 1.44 35.27 2.54 2.38 36.68 2.45 17.5738.85 2.32 2.01

Example 15

Preparation of Form CS1 of Ozanimod Hydrochloride:

5.4 mg of ozanimod hydrochloride was added into a 1.5-mL galss vialfollowed by adding 0.3 mL of solvent mixture of methanol and water (9:1,v/v) at 50° C. The mixture was filtered and fast cooled at −20° C. toobtain solid.

The obtained white solid was identified as Form CS1 of ozanimodhydrochloride. The XRPD data of the solid prepared in this example arelisted in Table 13. The XRPD pattern is displayed in FIG. 24.

TABLE 13 Relatively 2theta d spacing intensity % 3.92 22.54 56.68 7.9411.14 51.15 9.36 9.45 1.72 9.89 8.95 3.02 11.96 7.40 51.80 12.57 7.0411.98 13.04 6.79 15.16 13.79 6.42 12.00 15.96 5.55 3.10 16.95 5.23 3.2818.21 4.87 4.07 18.78 4.73 9.66 19.69 4.51 12.34 20.08 4.42 100.00 21.114.21 27.35 21.87 4.06 5.55 22.77 3.91 7.92 24.40 3.65 44.75 25.00 3.5610.24 26.13 3.41 43.35 26.80 3.33 6.64 27.91 3.20 6.55 28.96 3.08 3.9429.86 2.99 2.81 31.57 2.83 7.26 33.39 2.68 2.12 36.71 2.45 15.24

Example 16

Hygroscopicity Assessment of Form CS1 of Ozanimod:

Dynamic vapor sorption (DVS) was applied to test hygroscopicity of FormCS1 with about 10 mg of samples. The result is listed in Table 14. TheDVS plot is shown in FIG. 25.

TABLE 14 Crystal Form Weight gain under 80% RH Form CS1 0.36%

The results indicates that the weight gain of Form CS1 under 80% RH is0.36%. According to the definition of hygroscopicity, Form CS1 belongsto slightly hygroscopic.

Example 17

Hygroscopicity Assessment of Form CS2 of Ozanimod:

Dynamic vapor sorption (DVS) was applied to test hygroscopicity of FormCS2 with about 10 mg of samples. The result is listed in Table 15. TheDVS plot is shown in FIG. 26.

TABLE 15 Weight gain under 80% Crystal Form RH Form CS2 0.25%

The results indicates that the weight gain of Form CS2 under 80% RH is0.25%. According to the definition of hygroscopicity, Form CS2 belongsto slightly hygroscopic.

Example 18

Hygroscopicity Assessment of Form CS3 of Ozanimod:

Dynamic vapor sorption (DVS) was applied to test hygroscopicity of FormCS3 with about 10 mg of samples. The result is listed in Table 16. TheDVS plot is shown in FIG. 27.

TABLE 16 Weight gain under 80% Crystal Form RH Form CS3 2.25%

The results indicates that the weight gain of Form CS3 under 80% RH is2.25%.

Example 19

Hygroscopicity Assessment of Form CS5 of Ozanimod:

Dynamic vapor sorption (DVS) was applied to test hygroscopicity of FormCS5 with about 10 mg of samples. The result is listed in Table 17. TheDVS plot is shown in FIG. 28.

TABLE 17 Weight gain under 80% Crystal Form RH Form CS5 0.23%

The results indicates that the weight gain of Form CS5 under 80% RH is0.23%. According to the definition of hygroscopicity, Form CS5 belongsto slightly hygroscopic.

Example 20

Hygroscopicity Assessment of Form CS6 of Ozanimod:

Dynamic vapor sorption (DVS) was applied to test hygroscopicity of FormCS6 with about 10 mg of samples. The result is listed in Table 18. TheDVS plot is shown in FIG. 29.

TABLE 18 Weight gain under 80% Crystal Form Relative Humidity Form CS61.68%

The results indicates that the weight gain of Form CS6 under 80% RH is1.68%.

Example 21

Hygroscopicity Assessment of Form CS1 of Ozanimod Hydrochloride:

Dynamic vapor sorption (DVS) was applied to test hygroscopicity of FormCS1 of ozanimod hydrochloride with about 10 mg of samples. The result islisted in Table 19. The DVS plot is shown in FIG. 30.

TABLE 19 Weight gain under 80% Crystal Form Relative Humidity ozanimodhydrochloride 0.55% Form CS1

The results indicates that the weight gain of Form CS1 of ozanimodhydrochloride under 80% RH is 0.55%. According to the definitionstandard of hygroscopicity, ozanimod hydrochloride Form CS1 was slightlyhygroscopic.

Description and definition of hygroscopicity (Chinese Pharmacopoeia 2015edition appendix Drug hygroscopic test guidelines, test at 25° C.+/−1°C., 80% RH).

-   -   deliquescent: Sufficient water is absorbed to form a liquid;    -   very hygroscopic: Increase in mass is equal to or greater than        15 percent;    -   hygroscopic: Increase in mass is less than 15 percent and equal        to or greater than 2 percent;    -   slightly hygroscopic: Increase in mass is less than 2 percent        and equal to or greater than 0.2 percent.    -   non hygroscopic or almost non hygroscopic: Increase in mass is        less than 0.2 percent.

Example 22

Stability Assessment of Form CS1 of Ozanimod:

Three solid samples of Form CS1 were placed in constant temperature andhumidity chambers at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for4 weeks. XRPD was used to test the crystalline form at the end of week4. HPLC was used to measure the chemical purity at the end of week 1, 2,and 4. The XRPD comparison result is shown in FIG. 31 (from top tobottom: XRPD pattern of Form CS1 before and after being stored under 25°C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks), and the resultsare shown in Table 20.

TABLE 20 Change 1 week 2 week 4 week of the Initial purity purity puritycrystalline Form Conditions % % % form Form CS1 25° C./60% RH 99.1299.18 98.97 No change Form CS1 40° C./75% RH 99.16 99.17 98.92 No changeForm CS1 60° C./75% RH 99.26 99.13 98.71 No change

No form change and obvious purity decrease were observed for Form CS1after being stored at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for4 weeks. The result shows that Form CS1 has good stability.

Example 23

Stability Assessment of Form CS2 of Ozanimod:

Four solid samples of Form CS2 were placed in constant temperature andhumidity chambers at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for4 weeks and 80° C. for 1 week. XRPD was used to test the crystallineform at the end of week 4. HPLC was used to measure the chemical purityat the end of week 1, 2, and 4. The XRPD comparison result is shown inFIG. 32 (from top to bottom: XRPD pattern of Form CS2 before and afterbeing stored under 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4weeks and 80° C. for 1 week), and the results are shown in Table 21.

TABLE 21 Change 1 week 2 week 4 week of the Initial purity purity puritycrystalline Form Conditions % % % form Form CS2 25° C./60% RH 99.8599.63 99.62 No change Form CS2 40° C./75% RH 99.84 99.78 99.55 No changeForm CS2 60° C./75% RH 99.91 99.60 99.63 No change Form CS2 80° C. 99.71N/A N/A No change N/A indicates not tested in this embodiment.

No form change and obvious purity decrease were observed for Form CS2after being stored at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for4 weeks and 80° C. for 1 week. It can be seen that Form CS2 has goodstability.

Example 24

Stability Assessment of Form CS3 of Ozanimod:

Three solid samples of Form CS3 were placed in constant temperature andhumidity chambers at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for4 weeks. XRPD was used to test the crystalline form at the end of week4. HPLC was used to measure the chemical purity at the end of week 1, 2,and 4. The XRPD comparison pattern is shown in FIG. 33 (from top tobottom: XRPD pattern of Form CS3 before and after being stored under 25°C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks), and the resultsare shown in Table 22.

TABLE 22 Change 1 week 2 week 4 week of the Initial purity purity puritycrystalline Form Conditions % % % form Form CS3 25° C./60% RH 99.5399.30 99.31 No change Form CS3 40° C./75% RH 99.52 99.28 99.17 No changeForm CS3 60° C./75% RH 99.36 98.84 98.54 No change

No form change and obvious purity decrease were observed for Form CS3after being stored at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for4 weeks. It can be seen that Form CS3 has good stability.

Example 25

Stability Assessment of Form CS5 of Ozanimod:

Three solid samples of Form CS5 were placed in constant temperature andhumidity chambers at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for2 weeks. XRPD was used to test the crystalline form at the end of week4. The XRPD comparison pattern is shown in FIG. 34 (from top to bottom:XRPD pattern of Form CS5 before and after being stored under 25° C./60%RH, 40° C./75% RH and 60° C./75% RH for 2 weeks), and the results areshown in Table 23.

TABLE 23 Change of the Initial crystalline Form Conditions Time formForm CS5 25° C./60% RH 2 weeks No change Form CS5 40° C./75% RH 2 weeksNo change Form CS5 60° C./75% RH 2 weeks No change

No form change and obvious purity decrease was observed for Form CS5after being stored at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for2 weeks. It can be seen that Form CS5 has good stability.

Example 26

Stability Assessment of Form CS6 of Ozanimod:

Two samples of Form CS6 were placed in constant temperature and humiditychambers at 25° C./60% RH and 40° C./75% RH for 4 weeks. XRPD was usedto test the crystalline form at the end of week 4. HPLC was used tomeasure the chemical purity at the end of week 1, 2, and 4. The XRPDcomparison result is shown in FIG. 35 (from top to bottom: XRPD patternof Form CS6 before and after being stored under 25° C./60% RH and 40°C./75% RH for 4 weeks), and the results are shown in Table 24.

TABLE 24 Change 1 week 2 week 4 week of the Initial purity purity puritycrystalline Form Conditions % % % form Form CS6 25° C./60% RH 98.4498.21 98.27 No change Form CS6 40° C./75% RH 98.47 98.33 97.97 No change

No form change and obvious purity decrease were observed for Form CS6after being stored at 25° C./60% RH and 40° C./75% RH for 4 weeks. Itcan be seen that Form CS6 has good stability.

Example 27

Stability Assessment of Form CS1 of Ozanimod Hydrochloride:

Four samples of Form CS1 of ozanimod hydrochloride were placed inconstant temperature and humidity chambers at 25° C./60% RH, 40° C./75%RH and 60° C./75% RH for 4 weeks and 80° C. for 1 week. XRPD was used totest the crystalline form at the end of week 4. HPLC was used to measurethe chemical purity at the end of week 1, 2, and 4. The XRPD comparisonpattern is shown in FIG. 36 (from top to bottom: XRPD pattern ofozanimod hydrochloride Form CS1 before and after being stored under 25°C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks and 80° C. for 1week), and the results are shown in Table 25.

TABLE 25 Change 1 week 2 week 4 week of the purity purity puritycrystalline Initial Form Conditions % % % form Form CS1 of 25° C./ 99.1899.13 99.22 No change ozanimod 60% RH hydrochloride Form CS1 of 40° C./99.15 99.12 99.24 No change ozanimod 75% RH hydrochloride Form CS1 of60° C./ 99.25 99.25 99.36 No change ozanimod 75% RH hydrochloride FormCS1 of 80° C. 99.34 N/A N/A No change ozanimod hydrochloride

No form change and obvious purity decrease were observed for ozanimodhydrochloride Form CS1 after being stored at 25° C./60% RH, 40° C./75%RH and 60° C./75% RH for 4 weeks and 80° C. for 1 week. It can be seenthat Form CS1 of ozanimod hydrochloride has good stability.

Example 28

Particle Size Distribution:

Certain amount of samples of Form CS1, Form CS2, Form CS3, Form CS5,Form CS6 of ozanimod and Form CS1 of ozanimod hydrochloride were takenfor particle size distribution test. The results are shown in Table 26.

TABLE 26 Form MV(μm) SD D10 (μm) D50 (μm) D90 (μm) Form CS1 22.40 15.083.15 11.20 48.90 Form CS2 23.24 11.21 5.78 14.20 42.35 Form CS3 66.6239.31 20.36 51.80 130.8 Form CS5 68.84 61.69 6.55 41.10 173.3 Form CS668.91 54.79 12.87 46.47 161.7 Form CS1 of 200.7 168.4 20.84 180.8 397.7ozanimod hydrochloride Mv: Average particle size calculated by volume.SD: Standard deviation D10: particle size which accounts for 10% of theparticle size distribution (volume distribution). D50: particle sizewhich accounts for 50% of the particle size distribution (volumedistribution), also known as the median diameter. D90: particle sizewhich accounts for 90% of the particle size distribution (volumedistribution).

The particle size distribution diagram of Form CS1 is shown in FIG. 37.The result shows that the average particle size of Form CS1 is 22.40 μm,and the particle size distribution is narrow, which presents an almostnormal and uniform distribution.

The particle size distribution diagram of Form CS2 is shown in FIG. 38.The result shows that the average particle size of Form CS2 is 23.24 μm,and the particle size distribution is narrow, which presents an almostnormal and uniform distribution.

The particle size distribution diagram of Form CS3 is shown in FIG. 39.The result shows that the average particle size of Form CS3 is 66.62 μm,and the particle size distribution is narrow, which presents an almostnormal and uniform distribution.

The particle size distribution diagram of Form CS5 is shown in FIG. 40.The result shows that the average particle size of Form CS5 is 68.84 μm,and the particle size distribution is narrow, which presents an almostnormal and uniform distribution.

The particle size distribution diagram of Form CS6 is shown in FIG. 41.The result shows that the average particle size of Form CS6 is 68.91 μm,and the particle size distribution is narrow, which presents an almostnormal and uniform distribution.

The particle size distribution diagram of Form CS1 of ozanimodhydrochloride is shown in FIG. 42. The result shows that the averageparticle size of Form CS1 of ozanimod hydrochloride is 200.7 μm, and theparticle size is large which conducive to separation during production.

Furthermore, PLM plots of Form CS1, Form CS2, Form CS3, Form CS5, FormCS6 of ozanimod and Form CS1 of ozanimod hydrochloride were displayed inFIG. 43, FIG. 44, FIG. 45, FIG. 46, FIG. 47 and FIG. 48 respectively.Form CS3 was flake-like, Form CS1, Form CS2, Form CS5, Form CS6 and FormCS1 of ozanimod hydrochloride were short rod-like with good dispersion,less agglomeration and uniform particle size.

Uniform particle size helps to simplify the post-treatment process andimprove quality control.

Example 29

Solubility Assessment of Form CS1 of Ozanimod and Form CS1 of OzanimodHydrochloride:

Form CS1 and Form CS1 of ozanimod hydrochloride were suspended into SGF(Simulated gastric fluids) and FeSSIF (Fed state simulated intestinalfluids, pH=5.0) to obtain saturated solutions. After being equilibratedfor 1 h, 4 h and 24 h, concentrations of the saturated solutions weremeasured by HPLC. The results were listed in Table 27.

TABLE 27 Solubility (mg/mL) SGF FeSSIF Form CS1 of Form CS1 of ozanimodozanimod Time (h) Form CS1 hydrochloride Form CS1 hydrochloride 1 6.40.2 4.2 1.3 4 6.3 0.2 7.3 1.5 24 5.9 0.2 7.7 1.4

Example 30

Solubility Assessment:

Form CS3 and Form CS5 were suspended into SGF (Simulated gastric fluids)and water, and Form CS2 was suspended into FeSSIF (Fed state simulatedintestinal fluids) to obtain saturated solutions. After beingequilibrated for 1 h, 4 h and 24 h, concentrations of the saturatedsolutions were measured by HPLC. The results were listed in Table 28.

TABLE 28 Solubility (mg/mL) FeSSIF SGF H₂O Time (h) Form CS2 Form CS3Form CS5 Form CS3 Form CS5 1 2.0 0.54 1.4 0.17 0.24 4 2.2 0.52 1.0 0.240.26 24 1.1 0.54 0.77 0.35 0.27

Example 31

Mechanical Stability of Form CS3, Form CS5, Form CS6 of Ozanimod andForm CS1 of Ozanimod Hydrochloride:

Solid samples of Form CS3, Form CS5, Form CS6 of ozanimod and Form CS1of ozanimod hydrochloride were ground manually for 5 minutes in mortar.The XRPD patterns were displayed in FIG. 49, FIG. 50, FIG. 51 and FIG.52, respectively (the top pattern is before grinding and bottom patternis after grinding).

No form change was observed for Form CS3, Form CS5, Form CS6 of ozanimodand Form CS1 of ozanimod hydrochloride under a certain mechanical stresswith slightly decrease in crystallinity. Good physical and chemicalproperties including stability made these forms suitable for drugpreparation and storage.

Crystalline forms with better mechanical stability have goodphysicochemical properties and remain stable under certain mechanicalstress. The crystalline drug with better mechanical stability has lowrequirements on the crystallization equipment, and no specialpost-treatment condition is required. It is more stable in theformulation process, can significantly reduce the development cost ofthe drug products, enhance the quality of the drug, and has strongeconomic value.

It is to be noted that Form CS1 used in Examples 16 to 31 of the presentdisclosure is prepared by the method of Example 1; Form CS2 is preparedby the method of Example 3; Form CS3 was prepared by the method ofExample 6; Form CS5 was prepared by the method of Example 9; Form CS6was prepared by the method of Example 10; Form CS1 of ozanimodhydrochloride was prepared by the method of Example 11.

The examples described above are only for illustrating the technicalconcepts and features of the present disclosure, and intended to makethose skilled in the art being able to understand the present disclosureand thereby implement it, and should not be concluded to limit theprotective scope of this disclosure. Any equivalent variations ormodifications according to the spirit of the present disclosure shouldbe covered by the protective scope of the present disclosure.

The invention claimed is:
 1. A crystalline Form CS1 of ozanimod, whereinthe X-ray powder diffraction pattern shows characteristic peaks at2theta values of 12.1°±0.2°, 10.4°±0.2° and 4.2°±0.2° using CuKαradiation.
 2. The crystalline Form CS1 of ozanimod according to claim 1,wherein the X-ray powder diffraction pattern shows 1 or 2 or 3characteristic peaks at 2 theta values of 7.4°±0.2°, 24.3°±0.2° and17.7°±0.2° using CuKα radiation.
 3. The crystalline Form CS1 of ozanimodaccording to claim 1, wherein the X-ray powder diffraction pattern shows1 or 2 or 3 characteristic peaks at 2 theta values of 12.8°±0.2°,21.5°±0.2° and 18.2°±0.2° using CuKα radiation.
 4. A process forpreparing crystalline Form CS1 of ozanimod according to claim 1, whereinthe process comprises method 1) or method 2), 1) suspending ozanimodhydrochloride into a solvent selected from an alcohol, a ketone, anester, and a nitrile and stirring, adding 1.0 to 1.5 equivalent ofsodium hydroxide solution to the suspension to obtain a clear solution;after stirring the clear solution at room temperature, precipitating awhite solid from the solution, isolating, drying the solid to obtain awhite solid which is Form CS1 of ozanimod; wherein said stirring time isat least 0.5 hour; or 2) suspending ozanimod into an alcohol andstirring, isolating and drying the solid to obtain Form CS1 of ozanimod;wherein said stirring time is at least 0.5 hour, wherein said alcohol inmethod 1) or method 2) is methanol; said ketone is acetone; said esteris isopropyl acetate; said nitrile is acetonitrile.
 5. A crystallineForm CS2 of ozanimod, wherein the X-ray powder diffraction pattern showscharacteristic peaks at 2 theta values of 23.2°±0.2°, 18.5°±0.2° and13.3°±0.2° using CuKα radiation.
 6. The crystalline Form CS2 of ozanimodaccording to claim 5, wherein the X-ray powder diffraction pattern shows1 or 2 or 3 characteristic peaks at 2 theta values of 15.9°±0.2°,30.0°±0.2° and 14.2°±0.2° using CuKα radiation.
 7. The crystalline FormCS2 of ozanimod according to claim 5, wherein the X-ray powderdiffraction pattern shows 1 or 2 or 3 characteristic peaks at 2 thetavalues of 4.0°±0.2°, 26.5°±0.2° and 17.7°±0.2° using CuKα radiation. 8.A process for preparing crystalline Form CS2 of ozanimod according toclaim 5, wherein the process comprises method 1) or method 2), 1)Preparing the crystalline Form CS2 by heating Form CS1 of ozanimod ofwhich the X-ray powder diffraction pattern shows characteristic peaks at2 theta values of 12.1°±0.2°, 10.4°±0.2° and 4.2°±0.2° using CuKαradiation to 100-130° C.; or 2) Suspending ozanimod into a solventselected from a nitrile, a ketone, an ester, an aromatic hydrocarbon, acyclic ether, and water, or a mixture of solvents selected from analcohol and water, a ketone and water, an amide and water, stirring,isolating to obtain a solid, and drying the solid to obtain Form CS2 ofozanimod; wherein said stirring time is at least 0.5 hour.
 9. Acrystalline Form CS3 of ozanimod, wherein the X-ray powder diffractionpattern shows characteristic peaks at 2 theta values of 4.4°±0.2°,13.0°±0.2°, 26.0°±0.2° and 11.0°±0.2° using CuKα radiation.
 10. Thecrystalline Form CS3 of ozanimod according to claim 9, wherein the X-raypowder diffraction pattern shows 1 or 2 or 3 characteristic peaks at 2theta values of 7.8°±0.2°, 23.2°±0.2° and 17.0°±0.2° using CuKαradiation.
 11. The crystalline Form CS3 of ozanimod according to claim9, wherein the X-ray powder diffraction pattern shows 1 or 2characteristic peaks at 2 theta values of 13.7°±0.2° and 24.1°±0.2°using CuKα radiation.
 12. A process for preparing crystalline Form CS3of ozanimod according to claim 9, wherein the process comprises addingozanimod into a solvent selected from an alcohol, a nitrile,dichloromethane, an ester, or a sulfoxide, filtering, evaporating thefiltrate, and collecting the solid to obtain Form CS3 of ozanimod,wherein said alcohol is methanol; said nitrile is acetonitrile; saidester is isopropyl acetate; said sulfoxide is dimethyl sulfoxide.
 13. Acrystalline Form CS5 of ozanimod, wherein the X-ray powder diffractionpattern shows characteristic peaks at 2 theta values of 4.3°±0.2°,6.8°±0.2° and 16.4°±0.2° using CuKα radiation.
 14. The crystalline FormCS5 of ozanimod according to claim 13, wherein the X-ray powderdiffraction pattern shows 1 or 2 or 3 characteristic peaks at 2 thetavalues of 21.6°±0.2°, 8.5°±0.2° and 13.6°±0.2° using CuKα radiation. 15.The crystalline Form CS5 of ozanimod according to claim 13, wherein theX-ray powder diffraction pattern shows 1 or 2 or 3 characteristic peaksat 2 theta values of 13.0°±0.2°, 25.0°±0.2° and 26.0°±0.2° using CuKαradiation.
 16. A process for preparing crystalline Form CS5 of ozanimodaccording to claim 13, wherein the process comprises adding the solid ofozanimod into a cyclic ether, filtering, evaporating the filtrate andcollecting the solid to obtain Form CS5 of ozanimod, wherein said cyclicether is 2-methyltetrahydrofuran.
 17. A crystalline Form CS6 ofozanimod, wherein the X-ray powder diffraction pattern showscharacteristic peaks at 2 theta values of 4.4°±0.2°, 24.5±0.2°,26.5°±0.2° and 13.8°±0.2° using CuKα radiation.
 18. The crystalline FormCS6 of ozanimod according to claim 17, wherein the X-ray powderdiffraction pattern shows 1 or 2 characteristic peaks at 2 theta valuesof 13.0°±0.2° and 25.4±0.2° using CuKα radiation.
 19. The crystallineForm CS6 of ozanimod according to claim 17, wherein the X-ray powderdiffraction pattern shows 1 or 2 or 3 characteristic peaks at 2 thetavalues of 8.9°±0.2°, 13.4°±0.2° and 11.0°±0.2° using CuKα radiation. 20.A process for preparing crystalline Form CS6 of ozanimod according toclaim 17, wherein the process comprises adding solid of ozanimod into asolvent selected from a ketone and chloroform, filtering, evaporatingthe filtrate and collecting the solid to obtain Form CS6 of ozanimod,wherein said ketone is acetone.
 21. A pharmaceutical composition,wherein said pharmaceutical composition comprises a therapeuticallyeffective amount of crystalline Form CS2 of ozanimod according to claim5, and a pharmaceutically acceptable carrier, a diluent or an excipient.22. A method of treating ulcerative colitis, comprising administering toa patient in need thereof a therapeutically effective amount ofcrystalline Form CS2 of ozanimod according to claim
 5. 23. A method oftreating multiple sclerosis, comprising administering to a patient inneed thereof a therapeutically effective amount of crystalline Form CS2of ozanimod according to claim
 5. 24. A pharmaceutical composition,wherein said pharmaceutical composition comprises a therapeuticallyeffective amount of crystalline Form CS1 of ozanimod according to claim1, and a pharmaceutically acceptable carrier, a diluent or an excipient.25. A method of treating ulcerative colitis, comprising administering toa patient in need thereof a therapeutically effective amount ofcrystalline Form CS1 of ozanimod according to claim
 1. 26. A method oftreating multiple sclerosis, comprising administering to a patient inneed thereof a therapeutically effective amount of crystalline Form CS1of ozanimod according to claim
 1. 27. A pharmaceutical composition,wherein said pharmaceutical composition comprises a therapeuticallyeffective amount of crystalline Form CS3 of ozanimod according to claim9, and a pharmaceutically acceptable carrier, a diluent or an excipient.28. A method of treating ulcerative colitis, comprising administering toa patient in need thereof a therapeutically effective amount ofcrystalline Form CS3 of ozanimod according to claim
 9. 29. A method oftreating multiple sclerosis, comprising administering to a patient inneed thereof a therapeutically effective amount of crystalline Form CS3of ozanimod according to claim
 9. 30. A pharmaceutical composition,wherein said pharmaceutical composition comprises a therapeuticallyeffective amount of crystalline Form CS5 of ozanimod according to claim13, and a pharmaceutically acceptable carrier, a diluent or anexcipient.
 31. A method of treating ulcerative colitis, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of crystalline Form CS5 of ozanimod according to claim
 13. 32. Amethod of treating multiple sclerosis, comprising administering to apatient in need thereof a therapeutically effective amount ofcrystalline Form CS5 of ozanimod according to claim
 13. 33. Apharmaceutical composition, wherein said pharmaceutical compositioncomprises a therapeutically effective amount of crystalline Form CS6 ofozanimod according to claim 17, and a pharmaceutically acceptablecarrier, a diluent or an excipient.
 34. A method of treating ulcerativecolitis, comprising administering to a patient in need thereof atherapeutically effective amount of crystalline Form CS6 of ozanimodaccording to claim
 17. 35. A method of treating multiple sclerosis,comprising administering to a patient in need thereof a therapeuticallyeffective amount of crystalline Form CS6 of ozanimod according to claim17.
 36. A process for preparing crystalline Form CS3 of ozanimodaccording to claim 9, wherein the process comprises adding ozanimod intoa mixture of glycol dimethyl ether and water, filtering, evaporating thefiltrate, and collecting the solid to obtain Form CS3 of ozanimod.